Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling

Yang Gu,Yong Tian,Tiankun Lu,Nian Liu,Lei He,Jiahang Zhang,Jianyi Wang,Luyun He,Zusen Fan,Yanying Wang,Xiaoxiao Zhu

doi:10.1186/s12943-021-01435-2

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells also called cancer stem cells (CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. However, the role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive.MethodsCircRNAs highly conserved in humans and mice were identified from 3 primary HCC samples by circRNA array. The expression and function of circIPO11 were further evaluated by Northern blot, limiting dilution xenograft analysis, chromatin isolation by RNA purification-PCR assay (ChIRP) and HCC patient-derived tumor cells (PDC) models. CircIpo11 knockout (KO) mice were generated by a CRISPR/Cas9 technology.ResultsCircIPO11 is highly expressed in HCC tumor tissues and liver CSCs. CircIPO11 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, circIPO11 recruits TOP1 to GLI1 promoter to trigger its transcription, leading to the activation of Hedgehog signaling. Moreover, GLI1 is also highly expressed in HCC tumor tissues and liver CSCs, and TOP1 expression levels positively correlate with the metastasis, recurrence and survival of HCC patients. Additionally, circIPO11 knockout in mice suppresses the progression of chemically induced liver cancer development.ConclusionOur findings reveal that circIPO11 drives the self-renewal of liver CSCs and promotes the propagation of HCC via activating Hedgehog signaling pathway. Antisense oligonucleotides (ASOs) against circIPO11 combined with TOP1 inhibitor camptothecin (CPT) exert synergistic antitumor effect. Therefore, circIPO11 and the Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity
CircIPO11 is highly expressed in HCC tumors and liver cancer stem cells (CSCs) To identify the function circular RNA (circRNA) in the tumorigenesis of HCC, we conducted circRNA transcriptome analysis of human HCC tumor and peri-tumor tissues with human circRNA array (Arraystar)
CircIPO11 was mainly localized in the nucleus via in situ hybridization of HCC samples (Fig. 1H), nuclear-cytoplasmic separation assay (Fig. 1I) and Immunofluorescence staining of human tumor tissues (Fig. 1J)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells called cancer stem cells (CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. The role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive. Hepatocellular carcinoma (HCC), a major type of primary liver cancer, is the second leading cause of cancer-related deaths globally [1]. Two main biological characteristics of HCC are high recurrence and heterogeneity [4]. These CSCs display the ability to self-renew, differentiate, and form new tumors, accounting for resistance to traditional treatments and the high recurrence rate of HCC [6]. The mechanism of maintaining liver CSC self-renewal remains elusive

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Discussion

Conclusion